title: Novel 5-aryloxypyrimidine SEN1576 as a candidate for the treatment of Alzheimer's disease.
abstract: Prefibrillar assembly of amyloid-β (Aβ) is a major event underlying the development of neuropathology and dementia in Alzheimer's disease (AD). This study determined the neuroprotective properties of an orally bioavailable Aβ synaptotoxicity inhibitor, SEN1576. Binding of SEN1576 to monomeric Aβ 1-42 was measured using surface plasmon resonance. Thioflavin-T and MTT assays determined the ability of SEN1576 to block Aβ 1-42-induced aggregation and reduction in cell viability, respectively. In vivo long-term potentiation (LTP) determined effects on synaptic toxicity induced by intracerebroventricular (i.c.v.) injection of cell-derived Aβ oligomers. An operant behavioural schedule measured effects of oral administration following i.c.v. injection of Aβ oligomers in normal rats. SEN1576 bound to monomeric Aβ 1-42, protected neuronal cells exposed to Aβ 1-42, reduced deficits in in vivo LTP and behaviour. SEN1576 exhibits the necessary features of a drug candidate for further development as a disease modifying treatment for the early stages of AD-like dementia.
authors.affiliation: School of Psychology, Queen's University, Belfast BT7 1NN, UK.
authors.forename: Eugene
authors.initials: E
authors.lastname: O'Hare
authors.forename: David I C
authors.initials: DI
authors.lastname: Scopes
authors.forename: Eun-Mee
authors.initials: EM
authors.lastname: Kim
authors.forename: Philip
authors.initials: P
authors.lastname: Palmer
authors.forename: David
authors.initials: D
authors.lastname: Spanswick
authors.forename: Bridgeen
authors.initials: B
authors.lastname: McMahon
authors.forename: Hozefa
authors.initials: H
authors.lastname: Amijee
authors.forename: Edmund
authors.initials: E
authors.lastname: Nerou
authors.forename: J Mark
authors.initials: JM
authors.lastname: Treherne
authors.forename: Ross
authors.initials: R
authors.lastname: Jeggo
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D057967:Infusions, Intraventricular; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011743:Pyrimidines; C000593175:SEN1576; C075222:amyloid beta-protein (1-42)